We have previously described induction of a large population of autoreactive T cells in the course of an immune response to randomly chosen foreign antigens. These T cells appear to be MHC-specific and provide a non-specific helper function that serves to enhance proliferation and differentiation of activated B cells. Our experiments suggest a relationship between antigen-specific and autoreactive T cells in that initial induction of autoreactive T cells in vitro requires antigenic restimulation of primed lymph node cells. Autoreactive T cells may derive from antigen-specific precursors. Alternatively, antigen-specific T cells might be required to activate stimulators of autoreactive T cells. We propose experiments to distinguish between these and other possiblilities. We have selected lines of both autoreactive and antigen-specific T cells from clonies in soft agar. A general method for enumerating precursors to autoreactive T cells will be developed and further autoreactive clones will be isolated and characterized as to MHC-specificity. In order to determine the relative heterogeneity of autoreactive T cell clones directed against a specific I-A subregion haplotype, we will attempt to raise anti-receptor antibodies to individual clones in both syngeneic and allogeneic immunizations. The identification of autoreactive T cells in normal individuals raises important issues concerning regulation of expansion of such T cells in vivo and their possible role in expression of autoantibodies. We will address these issues first by defining any special requirements for stimulators of autoreactive T cells, one possible target of regulation. We will, in addition, characterize humoral or cellular regulatory mechanisms that may be activated by repeated transfers of non-tumorigenic clones of autoreactive T cells into syngeneic individuals.